Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Abstract

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori’s anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.

Inflammasomes contributing to inflammation in arthritis

“…Oridonin, a bitter tetracycline diterpenoid compound, was identified as the active compound of these plants extracts . While the mechanism of oridonin is still unclear, it was shown to inhibit the NLRP3 inflammasome . Oridonin decreased the ability of NLRP3 to interact with NEK7, a protein that may modulate its activation …”

“…While the mechanism of oridonin is still unclear, it was shown to inhibit the NLRP3 inflammasome . Oridonin decreased the ability of NLRP3 to interact with NEK7, a protein that may modulate its activation …”

“…160 While the mechanism of oridonin is still unclear, it was shown to inhibit the NLRP3 inflammasome. 161 Oridonin decreased the ability of NLRP3 to interact with NEK7, a protein that may modulate its activation. 161 OLT1177 is a small non-lipophilic molecule that was found to inhibit the NLRP3 inflammasome 162 and demonstrated suppressed joint inflammation in murine models of acute arthritis.…”

Synthesis of New Lathyrane Diterpenoid Derivatives from Euphorbia lathyris and Evaluation of Their Anti‐Inflammatory Activities

“…In the kingdom of natural products, terpenoids have emerged as one of the most important families because of their distinct biological activities and drug‐like properties . In China and other countries, many kinds of terpenoids have been found with good anti‐inflammatory activities and some of which were used clinically for treating inflammation ( Figure ) . Finding new anti‐inflammatory drugs from terpenoids is therefore a good strategy …”

“…[5,6] In China and other countries, many kinds of terpenoids have been found with good anti-inflammatory activities and some of which were used clinically for treating inflammation (Figure 1). [7][8][9][10][11][12] Finding new anti-inflammatory drugs from terpenoids is therefore a good strategy. [13] The seeds of Euphorbia lathyris are utilized as traditional Chinese medicine for treating terminal schistosomiasis, ascites, hydropsy, and snakebites.…”